1. Field Of The Invention
This invention relates to pharmaceutical compositions containing (-)-hydroxycitric acid useful for lowering elevated blood sugar levels and for improving glucose metabolism in individuals in need thereof.
2. Description Of Prior Art
Elevated and erratic blood sugar levels are components of the condition known as diabetes mellitus. This condition can be life-threatening and high glucose levels in the blood plasma (hyperglycemia) can lead to a number of chronic diabetes syndromes, for example, atherosclerosis, microangiopathy, peripheral neuropathy, kidney disorders and renal failure, cardiac disease, diabetic retinopathy and other ocular disorders, including blindness. A precursor to this condition, insulin resistance, may be a component in many age-related deteriorations and can result in alternating periods of both high and low blood sugar, uneven energy, obesity, hypertension and other disorders.
Diabetic conditions usually are treated medically in one of two ways. Insulin, the hormone which removes glucose from circulation, is supplied exogenously to treat the more severe cases in which the body's ability to produce this hormone is either impaired or nonexistent. Oral diabetes medications (such as sulphonylureas and biguanides) are also available. The drug metformin, a biguanide which is perhaps the safest and most successful of the usual oral hypoglycaemics, suppresses an elevated rate of basal hepatic glucose production. This mode of action in one of the more successful hypoglycaemic drugs underscores the fact that the inability to regulate and suppress hepatic glucose production is an important aspect of diabetes and prodiabetic conditions.
(-)-Hydroxycitric acid (abbreviated herein as HCA) a naturally-ocurring substance found chiefly in fruits of the species of Garcinia, and several synthetic derivatives of citric acid have been investigated extensively in regard to their ability to inhibit the production of fatty acids from carbohydrates, to suppress appetite, and to inhibit weight gain. (Sullivan, A. C., et al., American Journal of Clinical Nutrition 1977;30:767.) HCA has not previously been suggested as a compound with the ability to lower blood sugar levels and/or improve glucose metabolism.
Weight loss benefits were first ascribed to HCA, its salts and its lactone in U.S. Pat. No. 3,764,692 granted to John M. Lowenstein in 1973. The claimed mechanisms of action for HCA, most of which were originally put forth by researcher at the pharmaceutical film of Hoffmann-La Roche, have been summarized in at least two United States Patents. In U.S. Pat. No. 5,626,849 these mechanisms are given as follows: "(-) HCA reduces the conversion of carbohydrate calories into fats. It does this by inhibiting the actions of ATP-citrate lyase, the enzyme which converts citrate into fatty acids and cholesterol in the primary pathway of fat synthesis in the body. The actions of (-) HCA increase the production and storage of glycogen (which is found in the liver, small intestine and muscles of mammals) while reducing both appetite and weight gain. (-) Hydroxycitric acid also causes calories to be burned in an energy cycle similar to thermogenesis . . . (-) HCA also increases the clearance of LDL cholesterol . . . " U.S. Pat. No. 5,783,603 further argues that HCA serves to disinhibit the metabolic breakdown and oxidation of stored fat for fuel via its effects upon the compound malonyl CoA and that gluconeogenesis takes place as a result of this action. The position that HCA acts to unleash fatty acid oxidation by negating the effects of malonyl CoA with gluconeogenesis as a consequence (McCarty M F. Medical Hypotheses 1994;42:215-225) is maintained in U.S. Pat. No. 5,914,326.
Quite surprisingly, one pronounced effect of HCA--its hypoglycemic effect--has never been mentioned in the literature on the topic. Indeed, those who uphold that HCA is gluconeogenic in its actions and primarily useful for increasing ketogenesis, typically view it as potentially raising blood sugar levels rather than reducing them. The original pharmaceutical research on HCA performed at Hoffman-La Roche mentioned above failed to find significant changes in either blood glucose levels or blood insulin levels, undoubtedly in large part due to the fact that almost all of that research used diets which consisted largely of glucose (e.g., 70% glucose diets were typically employed to encourage lipogenesis).
Whether HCA influences blood sugar levels is of great importance for several reasons, two of which are of particular significance for the use of HCA. First, many or even most individuals with serious weight control issues are insulin resistant and maintain proper glucose control only through the release of elevated amounts of insulin. Second, a large fraction of diabetics are also obese. (DeFronzo R A, Ferinimmi E. Diabetes Care 1991;14:173-194.) Many researchers consider insulin resistance both a cause and an effect of excessive weight. It is a cause due to its impact, for instance, upon the body's ability to metabolize fatty acids for fuel. It is an effect due to the the often demonstrated actions of excessive weight in sustaining the conditions which are linked to the emergence of insulin resistance. (Cusin, Isabelle, et al., International Journal of Obesity 1992;16, Suppl. 4:S1-S11; Ravussin, Eric and Swinburn, Boyd A., The Lancet 1992;340:404-408.) If HCA can aid in the metabolic control of blood glucose levels, it can be used to help break this vicious cycle of insulin resistance found in both obesity and diabetes.
There is evidence from animal studies, but not from any good human study, that ingested HCA will lower blood lipids levels, and it is known that high levels of circulating free fatty acids are often related to insulin resistance and thereby to erratic blood glucose control. However, this is an indirect effect rather than a direct one; it is analogous to maintaining--accurately--that substantial weight loss improves insulin resistance in many individuals. However, neither of these effects (lowering of blood lipids and weight loss), both of which are ascribed to HCA in the literature, are what is defined medically as a hypoglycemic effect.
Hypoglycemic agents have direct effects upon blood glucose levels, often by inhibiting gluconeogenesis. The compound metformin is a classic example of of a hypoglycemic agent which reduces elevated rates of hepatic gluconeogenesis. Such an effect has never been suggested in the literature on HCA to be part of that compound's mode of action. Indeed, a very recent review which suggests the use of HCA as a component in the nutritional therapy for diabetes continues to focus entirely upon a reduction in serum free fatty acids with a likely increase in gluconeogenesis which must be counterbalanced by the ingestion of items such as chromium, biotin or metformin. (McCarty M F. Med Hypotheses 2000 Mar;54(3):483-487; U.S. Pat. No. 5,914,326.)
Only the potassium and sodium salts of HCA are absorbed well enough to be effective hypoglycemic agents at tolerable levels of ingestion. Reasons for this are given in the copending U.S. Patent Application "Potassium (-)-Hydroxycitric Acid Methods For Pharmaceutical Preparations For Stable And Controlled Delivery." The calcium salt of HCA is extremely widely sold in the United States in dosages ranging up to approximately 12 grams per day (providing roughly 6 grams of HCA), and yet there are no reports in the literature of this salt being useful as a hypoglycemic agent.
In contrast to experiences with the calcium salt, the impact of ingestion of appropriate amounts of the appropriate salts of HCA upon subjects with elevated blood sugars is to reduce serum glucose levels, potentially very rapidly. This is particularly important to those suffering from non-insulin-dependent diabetes mellitus (NIDDM); simultaneous storage and release of glucose is an aspect of this condition. Diabetics Type 1 can also be insulin resistant, and it may be possible to use HCA as a blood sugar lowering agent for these patients so as to reduce overall insulin usage inasmuch as elevated amounts of insulin are themselves damaging to the body. In other words, HCA might be used as a hypogylcemic agent for diabetes and in other conditions related to the "metabolic syndrome," also called "Syndrome X" and insulin resistance. No prior art suggests this type of effect upon glucose metabolism.